|Ultiva

Ultiva

Generic Name: remifentanil
Dosage Form: Injection

For IV Use Only

Ultiva Description

Ultiva (remifentanil hydrochloride) for Injection
is a µ-opioid agonist chemically designated as a 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic
acid methyl ester, hydrochloride salt, C20H28N2O5•HCl, with a molecular weight of 412.91.
It has the following chemical structure:

Ultiva is a sterile, nonpyrogenic, preservative-free,
white to off-white lyophilized powder for intravenous (IV) administration
after reconstitution and dilution. Each vial contains 1, 2, or 5 mg of remifentanil
base; 15 mg glycine; and hydrochloric acid to buffer the solutions to a nominal
pH of 3 after reconstitution. When reconstituted as directed, solutions of
Ultiva are clear and colorless and contain remifentanil hydrochloride (HCl)
equivalent to 1 mg/mL of remifentanil base. The pH of reconstituted solutions
of Ultiva ranges from 2.5 to 3.5. Remifentanil HCl has a pKa of 7.07. Remifentanil
HCl has an n-octanol:water partition coefficient of 17.9 at pH 7.3.

Ultiva - Clinical Pharmacology

Ultiva is a µ-opioid agonist with rapid onset
and peak effect, and short duration of action. The µ-opioid activity
of Ultiva is antagonized by opioid antagonists such as naloxone.

Unlike other opioids, Ultiva is rapidly metabolized by hydrolysis
of the propanoic acid-methyl ester linkage by nonspecific blood and tissue
esterases. Ultiva is not a substrate for plasma cholinesterase (pseudocholinesterase)
and, therefore, patients with atypical cholinesterase are expected to have
a normal duration of action.

Pharmacodynamics

The analgesic effects of Ultiva are rapid in onset
and offset. Its effects and side effects are dose dependent and similar to
other µ-opioids. Ultiva in humans has a rapid blood-brain equilibration
half-time of 1 ± 1 minutes (mean ± SD) and a rapid onset of action.
The pharmacodynamic effects of Ultiva closely follow the measured blood concentrations,
allowing direct correlation between dose, blood levels, and response. Blood
concentration decreases 50% in 3 to 6 minutes after a 1-minute infusion or
after prolonged continuous infusion due to rapid distribution and elimination
processes and is independent of duration of drug administration. Recovery
from the effects of Ultiva occurs rapidly (within 5 to 10 minutes). New steady-state
concentrations occur within 5 to 10 minutes after changes in infusion
rate. When used as a component of an anesthetic technique, Ultiva can be
rapidly titrated to the desired depth of anesthesia/analgesia (e.g., as required
by varying levels of intraoperative stress) by changing the continuous infusion
rate or by administering an IV bolus injection.

Hemodynamics

In premedicated patients undergoing anesthesia,
1-minute infusions of < 2 mcg/kg of Ultiva cause dose-dependent hypotension
and bradycardia. While additional doses > 2 mcg/kg (up to 30 mcg/kg)
do not produce any further decreases in heart rate or blood pressure, the
duration of the hemodynamic change is increased in proportion to the blood
concentrations achieved. Peak hemodynamic effects occur within 3 to 5 minutes
of a single dose of Ultiva or an infusion rate increase. Glycopyrrolate,
atropine, and vagolytic neuromuscular blocking agents attenuate the hemodynamic
effects associated with Ultiva. When appropriate, bradycardia and hypotension
can be reversed by reduction of the rate of infusion of Ultiva, or the dose
of concurrent anesthetics, or by the administration of fluids or vasopressors.

Respiration

Ultiva depresses respiration in a dose-related fashion.
Unlike other fentanyl analogs, the duration of action of Ultiva at a given
dose does not increase with increasing duration of administration, due to
lack of drug accumulation. When Ultiva and alfentanil were dosed to equal
levels of respiratory depression, recovery of respiratory drive after 3-hour
infusions was more rapid and less variable with Ultiva (see Figure 1).

Spontaneous
respiration occurs at blood concentrations of 4 to 5 ng/mL in the absence
of other anesthetic agents; for example, after discontinuation of a 0.25-mcg/kg/min
infusion of remifentanil, these blood concentrations would be reached in 2
to 4 minutes. In patients undergoing general anesthesia, the rate of respiratory
recovery depends upon the concurrent anesthetic; N2O < propofol< isoflurane (see CLINICAL TRIALS - Recovery).

Muscle Rigidity

Skeletal muscle rigidity can be caused by Ultiva
and is related to the dose and speed of administration. Ultiva may cause
chest wall rigidity (inability to ventilate) after single doses of > 1 mcg/kg
administered over 30 to 60 seconds or infusion rates > 0.1 mcg/kg/min;
peripheral muscle rigidity may occur at lower doses. Administration of doses< 1 mcg/kg may cause chest wall rigidity when given concurrently with a
continuous infusion of Ultiva. Prior or concurrent administration of a hypnotic
(propofol or thiopental) or a neuromuscular blocking agent may attenuate the
development of muscle rigidity. Excessive muscle rigidity can be treated
by decreasing the rate or discontinuing the infusion of Ultiva or by administering
a neuromuscular blocking agent.

Histamine Release

Assays of histamine in patients and normal volunteers
have shown no elevation in plasma histamine levels after administration of
Ultiva in doses up to 30 mcg/kg over 60 seconds.

Analgesia

Infusions of 0.05 to 0.1 mcg/kg/min, producing blood
concentrations of 1 to 3 ng/mL, are typically associated with analgesia
with minimal decrease in respiratory rate. Supplemental doses of 0.5 to 1
mcg/kg, incremental increases in infusion rate > 0.05 mcg/kg/min,
and blood concentrations exceeding 5 ng/mL (typically produced by infusions
of 0.2 mcg/kg/min) have been associated with transient and reversible respiratory
depression, apnea, and muscle rigidity.

Anesthesia

Ultiva is synergistic with the activity of hypnotics
(propofol and thiopental), inhaled anesthetics, and benzodiazepines (see CLINICAL TRIALS, PRECAUTIONS, and DOSAGE
AND ADMINISTRATION).

Age

The pharmacodynamic activity of Ultiva (as measured
by the EC50 for development of delta waves on the EEG) increases
with increasing age. The EC50 of remifentanil for this measure
was 50% less in patients over 65 years of age when compared to healthy volunteers
(25 years of age) (see DOSAGE AND ADMINISTRATION).

Gender

No differences have been shown in the pharmacodynamic
activity (as measured by the EEG) of Ultiva between men and women.

Drug Interactions

In animals the duration of muscle paralysis from
succinylcholine is not prolonged by remifentanil.

Intraocular Pressure

There was no change in intraocular pressure after
the administration of Ultiva prior to ophthalmic surgery under monitored anesthesia
care.

Cerebrodynamics

Under isoflurane-nitrous oxide anesthesia (PaCO2<
30 mmHg), a 1-minute infusion of Ultiva (0.5 or 1.0 mcg/kg) produced no change
in intracranial pressure. Mean arterial pressure and cerebral perfusion decreased
as expected with opioids. In patients receiving Ultiva and nitrous oxide
anesthesia, cerebrovascular reactivity to carbon dioxide remained intact.
In humans, no epileptiform activity was seen on the EEG (n = 44) at remifentanil
doses up to 8 mcg/kg/min.

Renal Dysfunction

The pharmacodynamics of Ultiva (ventilatory response
to hypercarbia) are unaltered in patients with end stage renal disease (creatinine
clearance < 10 mL/min).

Hepatic Dysfunction

The pharmacodynamics of Ultiva (ventilatory response
to hypercarbia) are unaltered in patients with severe hepatic dysfunction
awaiting liver transplant.

Pharmacokinetics

After IV doses administered over 60 seconds, the
pharmacokinetics of remifentanil fit a three-compartment model with a
rapid distribution half-life of 1 minute, a slower distribution half-life
of 6 minutes, and a terminal elimination half-life of 10 to 20 minutes.
Since the terminal elimination component contributes less than 10% of the
overall area under the concentration versus time curve (AUC), the effective
biological half-life of Ultiva is 3 to 10 minutes. This is similar to
the 3- to 10-minute half-life measured after termination of prolonged infusions
(up to 4 hours; see Figure 2) and correlates with recovery times observed
in the clinical setting after infusions up to 12 hours. Concentrations
of remifentanil are proportional to the dose administered throughout the recommended
dose range. The pharmacokinetics of remifentanil are unaffected by the presence
of renal or hepatic impairment.

Distribution

The initial volume of distribution (Vd)
of remifentanil is approximately 100 mL/kg and represents distribution
throughout the blood and rapidly perfused tissues. Remifentanil subsequently
distributes into peripheral tissues with a steady-state volume of distribution
of approximately 350 mL/kg. These two distribution volumes generally correlate
with total body weight (except in severely obese patients when they correlate
better with ideal body weight [IBW]). Remifentanil is approximately 70% bound
to plasma proteins of which two-thirds is binding to alpha-1-acid-glycoprotein.

Metabolism

Remifentanil is an esterase-metabolized opioid.
A labile ester linkage renders this compound susceptible to hydrolysis by
nonspecific esterases in blood and tissues. This hydrolysis results
in the production of the carboxylic acid metabolite (3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic
acid), and represents the principal metabolic pathway for remifentanil (>
95%). The carboxylic acid metabolite is essentially inactive (1/4600 as potent
as remifentanil in dogs) and is excreted by the kidneys with an elimination
half-life of approximately 90 minutes. Remifentanil is not metabolized by
plasma cholinesterase (pseudocholinesterase) and is not appreciably metabolized
by the liver or lung.

Elimination

The clearance of remifentanil in young, healthy
adults is approximately 40 mL/min/kg. Clearance generally correlates
with total body weight (except in severely obese patients when it correlates
better with IBW). The high clearance of remifentanil combined with a relatively
small volume of distribution produces a short elimination half-life of approximately
3 to 10 minutes (see Figure 2). This value is consistent with the time taken
for blood or effect site concentrations to fall by 50% (context-sensitive
half-times) which is approximately 3 to 6 minutes. Unlike other fentanyl
analogs, the duration of action does not increase with prolonged administration.

Figure 2. Mean Concentration
(sd) versus Time

Titration to Effect

The rapid elimination of remifentanil permits
the titration of infusion rate without concern for prolonged duration. In
general, every 0.1-mcg/kg/min change in the IV infusion rate will lead
to a corresponding 2.5-ng/mL change in blood remifentanil concentration within
5 to 10 minutes. In intubated patients only, a more rapid increase (within
3 to 5 minutes) to a new steady state can be achieved with a 1.0-mcg/kg bolus
dose in conjunction with an infusion rate increase.

Special Populations

Pediatrics

In pediatric patients, 5 days to 17 years of
age (n = 47), the clearance and volume of distribution of remifentanil were
increased in younger children and declined to young healthy adult values by
age 17. The average clearance of remifentanil in neonates (less than
2 months of age) was approximately 90.5 ± 36.8 mL/min/kg (mean ±
SD) while in adolescents (13 to 16 years) this value was 57.2 ±
21.1 mL/min/kg. The total (steady-state) volume of distribution in neonates
was 452 ± 144 mL/kg versus 223 ± 30.6 mL/kg in adolescents.
The half-life of remifentanil was the same in neonates and adolescents.
Clearance of remifentanil was maintained at or above normal adult values in
patients 5 days to 17 years of age.

Renal Impairment

The pharmacokinetic profile of Ultiva is not
changed in patients with end stage renal disease (creatinine clearance <
10 mL/min). In anephric patients, the half-life of the carboxylic acid metabolite
increases from 90 minutes to 30 hours. The metabolite is removed by hemodialysis
with a dialysis extraction ratio of approximately 30%.

Hepatic Impairment

The pharmacokinetics of remifentanil and its
carboxylic acid metabolite are unchanged in patients with severe hepatic impairment.

Elderly

The clearance of remifentanil is reduced (approximately
25%) in the elderly (> 65 years of age) compared to young adults (average
25 years of age). However, remifentanil blood concentrations fall as rapidly
after termination of administration in the elderly as in young adults.

Gender

There is no significant difference in the pharmacokinetics
of remifentanil in male and female patients after correcting for differences
in weight.

Obesity

There is no difference in the pharmacokinetics
of remifentanil in non-obese versus obese (greater than 30% over IBW) patients
when normalized to IBW.

Cardiopulmonary Bypass (CPB)

Remifentanil clearance is reduced by approximately
20% during hypothermic CPB.

Drug Interactions

Remifentanil clearance is not altered by concomitant
administration of thiopental, isoflurane, propofol, or temazepam during anesthesia.In vitro studies with atracurium,
mivacurium, esmolol, echothiophate, neostigmine, physostigmine, and midazolam
revealed no inhibition of remifentanil hydrolysis in whole human blood by
these drugs.

Clinical Trials

Ultiva was evaluated in 3341 patients undergoing general
anesthesia (n = 2706) and monitored anesthesia care (n = 639). These patients
were evaluated in the following settings: inpatient (n = 2079) which
included cardiovascular (n = 426), and neurosurgical (n = 61), and outpatient
(n = 1349). Four-hundred and eighty-six (486) elderly patients (age
range 66 to 90 years) and 410 pediatric patients (age range birth to
12 years) received Ultiva. Of the general anesthesia patients, 682 also received
Ultiva as an IV analgesic agent during the immediate postoperative period.

Induction and Maintenance of General Anesthesia-Inpatient/Outpatient

The efficacy of Ultiva was investigated in 1562
patients in 15 randomized, controlled trials as the analgesic component for
the induction and maintenance of general anesthesia. Eight of these studies
compared Ultiva to alfentanil and two studies compared Ultiva to fentanyl.
In these studies, doses of Ultiva up to the ED90 were compared
to recommended doses (approximately ED50) of alfentanil or fentanyl.

Induction of Anesthesia

Ultiva was administered with isoflurane, propofol,
or thiopental for the induction of anesthesia (n = 1562). The majority of
patients (80%) received propofol as the concurrent agent. Ultiva reduced
the propofol and thiopental requirements for loss of consciousness. Compared
to alfentanil and fentanyl, a higher relative dose of Ultiva resulted in fewer
responses to intubation (see Table 1). Overall, hypotension occurred in 5%
of patients receiving Ultiva compared to 2% of patients receiving the other
opioids.

Ultiva has been used as a primary
agent for the induction of anesthesia; however, it should not be used as a
sole agent because loss of consciousness cannot be assured and because of
a high incidence of apnea, muscle rigidity, and tachycardia. The administration
of an induction dose of propofol or thiopental or a paralyzing dose of a muscle
relaxant prior to or concurrently with Ultiva during the induction of anesthesia
markedly decreased the incidence of muscle rigidity from 20% to < 1%.

Table 1. Response
to Intubation (Propofol/Opioid Induction*)

Opioid Treatment Group/
(No. of Patients)

Initial Dose
(mcg/kg)

Pre-Intubation
Infusion Rate (mcg/kg/min)

No. (%) Muscle
Rigidity

No. (%) Hypotension
During Induction

No. (%) Response
to Intubation

* Propofol was titrated
to loss of consciousness. Not all doses of Ultiva
were equipotent to the comparator opioid.

† Differences were statistically significant (P< 0.02).

‡ Initial
doses greater than 1 mcg/kg are not recommended.

Study 1:Ultiva (35)Ultiva (35) Alfentanil
(35)

1120

0.10.41.0

1 (3%)3 (9%)2 (6%)

000

27 (77%)11 (31%)†26 (74%)

Study 2:Ultiva (116) Alfentanil (118)

125

0.51.0

9 (8%)6 (5%)

5 (4%)5 (4%)

17 (15%)†33 (28%)

Study 3:Ultiva (134) Alfentanil (66)

120

0.52.0

2 (1%)0

4 (3%)0

25 (19%)19 (29%)

Study 4:Ultiva (98)Ultiva (91) Fentanyl
(97)

1 2‡3

0.20.4NA

11 (11%)†11 (12%)†1 (1%)

2 (2%)2 (2%)1 (1%)

35 (36%)12 (13%)†29 (30%)

Use During Maintenance of Anesthesia

Ultiva was investigated in 929 patients in seven
well-controlled general surgery studies in conjunction with nitrous oxide,isoflurane, or propofol in both inpatient and outpatient settings. These
studies demonstrated that Ultiva could be dosed to high levels of opioid effect
and rapidly titrated to optimize analgesia intraoperatively without delaying
or prolonging recovery.

Compared to alfentanil
and fentanyl, these higher relative doses (ED90) of Ultiva resulted
in fewer responses to intraoperative stimuli (see Table 2) and a higher frequency
of hypotension (16% compared to 5% for the other opioids). Ultiva was infused
to the end of surgery, while alfentanil was discontinued 5 to 30 minutes before
the end of surgery as recommended. The mean final infusion rates of Ultiva
were between 0.25 and 0.48 mcg/kg/min.

Table 2. Intraoperative Responses*

Opioid Treatment Group/(No. of
Patients)

Concurrent Anesthetic

Post-IntubationInfusion Rate (mcg/kg/min)

No. (%) With Intraoperative
Hypotension

No. (%) With Response
to Skin Incision

No. (%) With Signs
of Light Anesthesia

No. (%) With Response
to Skin Closure

*
Not all doses of Ultiva were equipotent to the comparator opioid.

† Differences were statistically
significant (P< 0.05).

Study 1:Ultiva (35)Ultiva
(35) Alfentanil (35)

Nitrous oxide

0.10.41.0

000

20 (57%)3 (9%)†24
(69%)

33 (94%)12 (34%)†33
(94%)

6 (17%)2 (6%)†12 (34%)

Study 2:Ultiva (116) Alfentanil
(118)

Isoflurane + Nitrous oxide

0.250.5

35 (30%)†12 (10%)

9 (8%)†20 (17%)

66 (57%)†85 (72%)

19 (16%)25 (21%)

Study 3:Ultiva (134) Alfentanil
(66)

Propofol

0.52.0

3 (2%)2 (3%)

14 (11%)†21 (32%)

70 (52%)†47 (71%)

25 (19%)13 (20%)

Study 4:Ultiva (98)Ultiva
(91) Fentanyl (97)

Isoflurane

0.20.41.5-3 mcg/kg prn

13 (13%)16 (18%)†7
(7%)

12 (12%)†4 (4%)†32
(33%)

67 (68%)†44 (48%)†84
(87%)

7 (7%)3 (3%)†11 (11%)

In three randomized, controlled studies
(n = 407) during general anesthesia, Ultiva attenuated the signs of light
anesthesia within a median time of 3 to 6 minutes after bolus doses of 1 mcg/kg
with or without infusion rate increases of 50% to 100% (up to a maximum rate
of 2 mcg/kg/min).

In an additional double-blind,
randomized study (n = 103), a constant rate (0.25 mcg/kg/min) of Ultiva
was compared to doubling the rate to 0.5 mcg/kg/min approximately 5 minutes
before the start of the major surgical stress event. Doubling the rate decreased
the incidence of signs of light anesthesia from 67% to 8% in patients undergoing
abdominal hysterectomy, and from 19% to 10% in patients undergoing radical
prostatectomy. In patients undergoing laminectomy the lower dose was adequate.

Recovery

In 2169 patients receiving Ultiva for periods up
to 16 hours, recovery from anesthesia was rapid, predictable, and independent
of the duration of the infusion of Ultiva. In the seven controlled, general
surgery studies, extubation occurred in a median of 5 minutes (range:
-3 to 17 minutes in 95% of patients) in outpatient anesthesia and 10 minutes
(range: 0 to 32 minutes in 95% of patients) in inpatient anesthesia. Recovery
in studies using nitrous oxide or propofol was faster than in those using
isoflurane as the concurrent anesthetic. There was no case of remifentanil-induced
delayed respiratory depression occurring more than 30 minutes after discontinuation
of remifentanil (see PRECAUTIONS).

In a double-blind, randomized study, administration of morphine
sulfate (0.15 mg/kg) intravenously 20 minutes before the anticipated
end of surgery to 98 patients did not delay recovery of respiratory drive
in patients undergoing major surgery with remifentanil-propofol total IV anesthesia.

Spontaneous Ventilation Anesthesia

Two randomized, dose-ranging studies (n = 127) examined
the administration of Ultiva to outpatients undergoing general anesthesia
with a laryngeal mask. Starting infusion rates of Ultiva of ≤ 0.05
mcg/kg/min provided supplemental analgesia while allowing spontaneous ventilation
with propofol or isoflurane. Bolus doses of Ultiva
during spontaneous ventilation lead to transient periods of apnea, respiratory
depression, and muscle rigidity.

Pediatric Anesthesia

Ultiva has been evaluated for maintenance of general
anesthesia in 410 pediatric patients from birth to 12 years undergoing inpatient
and outpatient procedures. Four clinical trials have been performed.

Study 1, an open-label, randomized, controlled clinical
trial (n = 129), compared Ultiva (n = 68) with alfentanil (n = 19),
isoflurane (n = 22), or propofol (n = 20) in children 2 to 12 years of age
undergoing strabismus surgery. After induction of anesthesia which included
the administration of atropine, Ultiva was administered as an initial infusion
of 1 mcg/kg/min with 70% nitrous oxide. The infusion rate required during
maintenance of anesthesia was 0.73 to 1.95 mcg/kg/min. Time to extubation
and to purposeful movement was a median of 10 minutes (range 1 to 24 minutes).

Study 2, a double-blind, randomized, controlled trial (n
= 222), compared Ultiva (n = 119) to fentanyl (n = 103) in children
2 to 12 years of age undergoing tonsillectomy with or without adenoidectomy.
After induction of anesthesia, patients received a 0.25 mcg/kg/min infusion
of Ultiva or fentanyl by IV bolus with nitrous oxide/oxygen (2:1) and either
halothane or sevoflurane for maintenance of anesthesia. The mean infusion
rate required during maintenance of anesthesia was 0.3 mcg/kg/min (range 0.2 to
1.3 mcg/kg/min). The continuous infusion rate was decreased to 0.05 mcg/kg/min
approximately 10 minutes prior to the end of surgery. Time to spontaneous
purposeful movement was a median of 8 minutes (range 1 to 19 minutes). Time
to extubation was a median of 9 minutes (range 2 to 19 minutes).

Study 3, an open-label, randomized, controlled trial (n
= 271), compared Ultiva (n = 185) with a regional anesthetic technique
(n = 86) in children 1 to 12 years of age undergoing major abdominal, urological,
or orthopedic surgery. Patients received a 0.25 mcg/kg/min infusion
of Ultiva following a 1.0 mcg/kg bolus or bupivacaine by epidural infusion,
along with isoflurane and nitrous oxide after the induction of anesthesia.
The mean infusion rate required during maintenance of anesthesia was 0.25 mcg/kg/min
(range 0 to 0.75 mcg/kg/min). Both treatments were effective in attenuating
responses to skin incision during surgery. The hemodynamic profile of the
Ultiva group was consistent with an opioid-based general anesthetic technique.
Time to spontaneous purposeful movement was a median of 15 minutes (range,
2 to 75 minutes) in the remifentanil group. Time to extubation was a median
of 13 minutes (range, 4 to 31 minutes) in the remifentanil group.

Study 4, an open-label, randomized, controlled trial (n=60),
compared Ultiva (n = 38) with halothane (n = 22) in ASA 1 or 2, full term
neonates and infants ≤8 weeks of age weighing at least 2500 grams who
were undergoing pyloromyotomy. After induction of anesthesia, which included
the administration of atropine, patients received 0.4 mcg/kg/min of Ultiva
or 0.4% halothane with 70% nitrous oxide for initial maintenance of anesthesiaand then both agents were adjusted according to clinical response. Bolus doses
of 1 mcg/kg administered over 30 to 60 seconds were used to treat brief episodes
of hypertension and tachycardia, and infusion rates were increased by 50%
to treat sustained hypertension and tachycardia. The range of infusion rates
of Ultiva required during maintenance of anesthesia was 0.4 to 1 mcg/kg/min.
[Seventy-one percent (71%) of Ultiva patients required supplementary boluses
or rate increases from the starting dose of 0.4 mcg/kg/min to treat hypertension,
tachycardia, movement or somatic signs of light anesthesia. Twenty-four percent
of the patients required an increase from the initial rate of 0.4 mcg/kg/min
prior to incision and 26% of patients required an infusion rate between 0.8
and 1.0 mcg/kg/min, most often during gastric manipulation. The continuous
infusion rate was decreased to 0.05 mcg/kg/min approximately 10 minutes
before the end of surgery. In the Ultiva group, median time from discontinuation
of anesthesia to spontaneous purposeful movement was 6.5 minutes (range, 1
to 13 minutes) and median time to extubation was 8.5 minutes (range, 1 to
14 minutes). The initial maintenance infusion regimen of Ultiva evaluated
in pediatric patients from birth to 2 months of age was 0.4 mcg/kg/min,
the approved adult regimen for use with N2O. The clearance rate
observed in the neonatal population was highly variable and on average was
two times higher than in the young healthy adult population. Therefore, while
a starting infusion of 0.4 mcg/kg/min may be appropriate for some neonates,
an increased infusion rate may be necessary to maintain adequate surgical
anesthesia, and additional bolus doses may be required. The individual dose
for each patient should be carefully titrated. (see CLINICAL
PHARMACOLOGY - Special Populations - Pediatric
Patients, and DOSAGE AND ADMINISTRATION, Table 11).

The first comparator
study, a multi-center, randomized, double-blind, double-dummy, parallel-group
study (N = 369), compared Ultiva (n = 201) with fentanyl (n = 168) in adult
patients undergoing elective CABG surgery. Subjects received 1 to 3-mg midazolam
and 0.05-mg/kg morphine IV as premedication. Anesthesia was induced with
propofol 0.5 mg/kg (higher doses administered with Ultiva were associated
with excessive hypotension) over one minute plus 10-mg boluses every 10 seconds
until loss of consciousness followed by either cisatracurium 0.2 mg/kg
or vecuronium 0.15 mg/kg. Patients randomized to Ultiva received a 1 mcg/kg/min
infusion of Ultiva followed by a placebo bolus administered over 3 minutes.
In the active control group, a placebo IV infusion was started and a fentanyl
bolus 10 mcg/kg was administered over 3 minutes. All subjects received
isoflurane titrated initially to end tidal concentration of 0.5%. During
maintenance, the group randomized to Ultiva received as needed 0.5-1 mcg/kg/min
IV rate increases (to a maximum of 4 mcg/kg/min) of Ultiva and 1 mcg/kg
IV boluses of Ultiva. The active control group received 2 mcg/kg IV boluses
of fentanyl and increases in placebo IV infusion rate.

The second comparator study, a multi-center, double-blind, randomized,
parallel group study (N = 57), compared Ultiva (n = 35) to fentanyl (n = 22)
in adult patients undergoing elective CABG surgery with poor left ventricular
function (ejection fraction < 0.35). Subjects received oral lorazepam
40 mcg/kg as premedication. Anesthesia was induced using etomidate until
loss of consciousness, followed by a low-dose propofol infusion (3 mg/kg/hr)
and pancuronium 0.15 mg/kg. Subjects in the group administered Ultiva
received a placebo bolus dose and a continuous infusion of Ultiva 1 mcg/kg/min
and subjects in the fentanyl group received a bolus loading dose of 15 mcg/kg
and placebo continuous infusion. During maintenance, supplemental bolus doses
of Ultiva (0.5 mcg/kg) and infusion rate increases of 0.5 to 1 mcg/kg/min
(maximum rate allowed was 4 mcg/kg/min) of Ultiva were administered to one
group; while the fentanyl group was given intermittent maintenance bolus doses
of 2 mcg/kg and increases in the placebo infusion rate.

In these two studies, using a high dose opioid technique with
Ultiva as a component of a balanced or total intravenous anesthetic regimen,
the remifentanil regimen effectively attenuated response to maximal sternal
spread generally better than the dose and regimen studied for the active control
(fentanyl). While this provides evidence for the efficacy of remifentanil
as an analgesic in this setting, caution must be exercised in interpreting
these results as evidence of superiority of remifentanil over the active control,
since these studies did not make any attempt to evaluate and compare the optimal
analgesic doses of either drug in this setting.

Neurosurgery

Ultiva was administered to 61 patients undergoing
craniotomy for removal of a supratentorial mass lesion. In these studies,
ventilation was controlled to maintain a predicted PaCO2 of approximately
28 mmHg. In one study (n = 30) with Ultiva and 66% nitrous oxide, the median
time to extubation and to patient response to verbal commands was 5 minutes
(range -1 to 19 minutes). Intracranial pressure and cerebrovascular
responsiveness to carbon dioxide were normal (see CLINICAL
PHARMACOLOGY).

A randomized, controlled
study compared Ultiva (n = 31) to fentanyl (n = 32). Ultiva (1 mcg/kg/min)
and fentanyl (2 mcg/kg/min) were administered after induction with thiopental
and pancuronium. A similar number of patients (6%) receiving Ultiva and fentanyl
had hypotension during induction. Anesthesia was maintained with nitrous
oxide and Ultiva at a mean infusion rate of 0.23 mcg/kg/min (range 0.1 to
0.4) compared with a fentanyl mean infusion rate of 0.04 mcg/kg/min (range
0.02 to 0.07). Supplemental isoflurane was administered as needed. The patients
receiving Ultiva required a lower mean isoflurane dose (0.07 MAC-hours) compared
with 0.64 MAC-hours for the fentanyl patients (P = 0.04). Ultiva was discontinued at the end of anesthesia,
whereas fentanyl was discontinued at the time of bone flap replacement (a median
time of 44 minutes before the end of surgery). Median time to extubation
was similar (5 and 3.5 minutes, respectively, with Ultiva and fentanyl).
None of the patients receiving Ultiva required naloxone compared to seven
of the fentanyl patients (P = 0.01).
Eighty-one percent (81%) of patients receiving Ultiva recovered (awake, alert,
and oriented) within 30 minutes after surgery compared with 59% of fentanyl
patients (P = 0.06). At 45 minutes,
recovery rates were similar (81% and 69% respectively for Ultiva and fentanyl, P = 0.27). Patients receiving Ultiva required
an analgesic for headache sooner than fentanyl patients (median of 35 minutes
compared with 136 minutes, respectively [P =
0.04]). No adverse cerebrovascular effects were seen in this study (see CLINICAL PHARMACOLOGY).

Continuation of Analgesic Use into the Immediate Postoperative Period

Analgesia with Ultiva in the immediate postoperative
period (until approximately 30 minutes after extubation) was studied
in 401 patients in four dose-finding studies and in 281 patients in two efficacy
studies. In the dose-finding studies, the use of bolus doses of Ultiva and
incremental infusion rate increases ≥ 0.05 mcg/kg/min led to respiratory
depression and muscle rigidity. Bolus doses of
Ultiva to treat postoperative pain are not recommended and incremental infusion
rate increases should not exceed 0.025 mcg/kg/min at 5-minute intervals.

In two efficacy studies, Ultiva 0.1
mcg/kg/min was started immediately after discontinuing anesthesia. Incremental
infusion rate increases of 0.025 mcg/kg/min every 5 minutes were given to
treat moderate to severe postoperative pain. In Study 1, 50% decreases in
infusion rate were made if respiratory rate decreased below 12 breaths/min
and in Study 2, the same decreases were made if respiratory rate was below
8 breaths/min. With this difference in criteria for infusion rate decrease,
the incidence of respiratory depression was lower in Study 1 (4%) than in
Study 2 (12%). In both studies, Ultiva provided effective analgesia (no or
mild pain with respiratory rate ≥ 8 breaths/min) in approximately
60% of patients at mean final infusion rates of 0.1 to 0.125 mcg/kg/min.

Study 2 was a double-blind, randomized, controlled study
in which patients received either morphine sulfate (0.15 mg/kg administered
20 minutes before the anticipated end of surgery plus 2-mg bolus doses for
supplemental analgesia) or Ultiva (as described above). Emergence from anesthesia
was similar between groups; median time to extubation was 5 to 6 minutes for
both. Ultiva provided effective analgesia in 58% of patients compared to
33% of patients who received morphine. Respiratory depression occurred in
12% of patients receiving Ultiva compared to 4% of morphine patients. For
patients who received Ultiva, morphine sulfate (0.15 mg/kg) was administered
in divided doses 5 and 10 minutes before discontinuing Ultiva. Within 30
minutes after discontinuation of Ultiva, the percentage of patients with effective
analgesia decreased to 34%.

Monitored Anesthesia Care

Ultiva has been studied in the monitored anesthesia
care setting in 609 patients in eight clinical trials. Nearly all patients
received supplemental oxygen in these studies. Two early dose-finding studies
demonstrated that use of sedation as an endpoint for titration of Ultiva led
to a high incidence of muscle rigidity (69%) and respiratory depression.
Subsequent trials titrated Ultiva to specific clinical endpoints of patient
comfort, analgesia, and adequate respiration (respiratory rate > 8 breaths/min)
with a corresponding lower incidence of muscle rigidity (3%) and respiratory
depression. With doses of midazolam > 2 mg (4 to 8 mg), the dose of
Ultiva could be decreased by 50%, but the incidence of respiratory depression
rose to 32%.

The efficacy of a single dose
of Ultiva (1.0 mcg/kg over 30 seconds) was compared to alfentanil (7 mcg/kg
over 30 seconds) in patients undergoing ophthalmic surgery. More patients
receiving Ultiva were pain free at the time of the nerve block (77% versus
44%, P = 0.02) and more experienced
nausea (12% versus 4%) than those receiving alfentanil.

In a randomized, controlled study (n = 118), Ultiva 0.5 mcg/kg
over 30 to 60 seconds followed by a continuous infusion of 0.1 mcg/kg/min,
was compared to a propofol bolus (500 mcg/kg) followed by a continuous
infusion (50 mcg/kg/min) in patients who received a local or regional anesthetic
nerve block 5 minutes later. The incidence of moderate or severe pain during
placement of the block was similar between groups (2% with Ultiva and 8% with
propofol, P = 0.2) and more
patients receiving Ultiva experienced nausea (26% versus 2%, P< 0.001). The final mean infusion rate of Ultiva was 0.08
mcg/kg/min.

In a randomized, double-blind study,
Ultiva with or without midazolam was evaluated in 159 patients undergoing
superficial surgical procedures under local anesthesia. Ultiva was administered
without midazolam as a 1-mcg/kg dose over 30 seconds followed by a continuous
infusion of 0.1 mcg/kg/min. In the group of patients that received midazolam,
Ultiva was administered as a 0.5-mcg/kg dose over 30 seconds followed by a
continuous infusion of 0.05 mcg/kg/min and midazolam 2 mg was administered
5 minutes later. The occurrence of moderate or severe pain during the local
anesthetic injection was similar between groups (16% and 20%). Other effects
for Ultiva alone and Ultiva/midazolam were: respiratory depression with oxygen
desaturation (SPO2 < 90%), 5% and 2%; nausea, 8% and 2%; and
pruritus, 23% and 12%. Titration of Ultiva resulted in prompt resolution
of respiratory depression (median 3 minutes, range 0 to 6 minutes).
The final mean infusion rate of Ultiva was 0.12 mcg/kg/min (range 0.03 to
0.3) for the group receiving Ultiva alone and 0.07 mcg/kg/min (range
0.02 to 0.2) for the group receiving Ultiva/midazolam.

Because of the risk for hypoventilation,
the infusion rate of Ultiva should be decreased to 0.05 mcg/kg/min following
placement of the local or regional block and titrated thereafter in increments
of 0.025 mcg/kg/min at 5-minute intervals. Bolus doses of Ultiva administered
simultaneously with a continuous infusion of Ultiva to spontaneously breathing
patients are not recommended.

Indications and Usage for Ultiva

Ultiva is indicated for IV administration:

As an analgesic agent for use during the induction and maintenance of
general anesthesia for inpatient and outpatient procedures.

For continuation as an analgesic into the immediate postoperative period
in adult patients under the direct supervision of an anesthesia practitioner
in a postoperative anesthesia care unit or intensive care setting.

As an analgesic component of monitored anesthesia care in adult patients.

Contraindications

Due to the presence of glycine in the formulation,
Ultiva is contraindicated for epidural or intrathecal administration. Ultiva
is also contraindicated in patients with known hypersensitivity to fentanyl
analogs.

Warnings

Continuous infusions of Ultiva should be administered
only by an infusion device. IV bolus administration
of Ultiva should be used only during the maintenance of general anesthesia.In nonintubated patients, single doses of Ultiva should be administered
over 30 to 60 seconds.

Interruption
of an infusion of Ultiva will result in rapid offset of effect. Rapid clearance
and lack of drug accumulation result in rapid dissipation of respiratory depressant
and analgesic effects upon discontinuation of Ultiva at recommended doses.
Discontinuation of an infusion of Ultiva should be preceded by the establishment
of adequate postoperative analgesia.

Injections
of Ultiva should be made into IV tubing at or close to the venous cannula.
Upon discontinuation of Ultiva, the IV tubing should be cleared to prevent
the inadvertent administration of Ultiva at a later point in time. Failure to adequately clear the IV tubing to remove residual
Ultiva has been associated with the appearance of respiratory depression,
apnea, and muscle rigidity upon the administration of additional fluids or
medications through the same IV tubing.

USE OF Ultiva IS ASSOCIATED WITH APNEA AND RESPIRATORY DEPRESSION.
Ultiva SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE
USE OF ANESTHETIC DRUGS AND THE MANAGEMENT OF THE RESPIRATORY EFFECTS OF POTENT
OPIOIDS, INCLUDING RESPIRATORY AND CARDIAC RESUSCITATION OF PATIENTS IN THE
AGE GROUP BEING TREATED. SUCH TRAINING MUST INCLUDE THE ESTABLISHMENT AND
MAINTENANCE OF A PATENT AIRWAY AND ASSISTED VENTILATION.

Ultiva SHOULD NOT BE USED IN DIAGNOSTIC OR THERAPEUTIC PROCEDURES
OUTSIDE THE MONITORED ANESTHESIA CARE SETTING. PATIENTS RECEIVING MONITORED
ANESTHESIA CARE SHOULD BE CONTINUOUSLY MONITORED BY PERSONS NOT INVOLVED IN
THE CONDUCT OF THE SURGICAL OR DIAGNOSTIC PROCEDURE. OXYGEN SATURATION SHOULD
BE MONITORED ON A CONTINUOUS BASIS.

RESUSCITATIVE
AND INTUBATION EQUIPMENT, OXYGEN, AND AN OPIOID ANTAGONIST MUST BE READILY
AVAILABLE.

Respiratory depression in spontaneously
breathing patients is generally managed by decreasing the rate of the infusion
of Ultiva by 50% or by temporarily discontinuing the infusion.

Skeletal muscle rigidity can be caused by Ultiva and is related
to the dose and speed of administration. Ultiva may cause chest wall rigidity
(inability to ventilate) after single doses of > 1 mcg/kg administered
over 30 to 60 seconds, or after infusion rates > 0.1 mcg/kg/min.
Single doses < 1 mcg/kg may cause chest wall rigidity when given
concurrently with a continuous infusion of Ultiva.

Muscle
rigidity induced by Ultiva should be managed in the context of the patient"s
clinical condition. Muscle rigidity occurring during the induction of anesthesia
should be treated by the administration of a neuromuscular blocking agent
and the concurrent induction medications.

Muscle
rigidity seen during the use of Ultiva in spontaneously breathing patients
may be treated by stopping or decreasing the rate of administration of Ultiva.
Resolution of muscle rigidity after discontinuing the infusion of Ultiva
occurs within minutes. In the case of life-threatening muscle rigidity, a
rapid onset neuromuscular blocker or naloxone may be administered.

Ultiva should not be administered into the same IV tubing
with blood due to potential inactivation by nonspecific esterases in blood
products.

Precautions

Vital signs and oxygenation must be continually monitored
during the administration of Ultiva.

General

Bradycardia has been reported with Ultiva and is responsive
to ephedrine or anticholinergic drugs, such as atropine and glycopyrrolate.

Hypotension has been reported with Ultiva and is responsive
to decreases in the administration of Ultiva or to IV fluids or catecholamine
(ephedrine, epinephrine, norepinephrine, etc.) administration.

Intraoperative awareness has been reported in patients under
55 years of age when Ultiva has been administered with propofol infusion rates
of ≤ 75 mcg/kg/min.

Rapid Offset of Action

WITHIN 5 TO
10 MINUTES AFTER THE DISCONTINUATION OF Ultiva, NO RESIDUAL ANALGESIC ACTIVITY
WILL BE PRESENT. However, respiratory depression may occur in some
patients up to 30 minutes after termination of infusion due to residual effects
of concomitant anesthetics. Standard monitoring should be maintained in the
postoperative period to ensure adequate recovery without stimulation. For
patients undergoing surgical procedures where postoperative pain is generally
anticipated, other analgesics should be administered prior to the discontinuation
of Ultiva.

Ultiva should not be used as a sole
agent for induction of anesthesia because loss of consciousness cannot be
assured and because of a high incidence of apnea, muscle rigidity, and tachycardia.

Pediatric Use

The efficacy and safety of Ultiva as an analgesic
agent for use in the maintenance of general anesthesia in outpatient and inpatient
pediatric surgery have been established in controlled clinical trials in pediatric
patients from birth to 12 years (see CLINICAL TRIALS).

The initial maintenance infusion
regimen of Ultiva evaluated in pediatric patients from birth to 2 months of
age was 0.4 mcg/kg/min, the approved adult regimen for use with N2O.
The clearance rate observed in neonates was highly variable and on average
was two times higher than in the young healthy adult population. Therefore,
while a starting infusion rate of 0.4 mcg/kg/min may be appropriate for some
neonates, an increased infusion rate may be necessary to maintain adequate
surgical anesthesia, and additional bolus doses may be required. The individual
dose for each patient should be carefully titrated. (see CLINICAL
PHARMACOLOGY - Special Populations - Pediatric
Patients, and DOSAGE AND ADMINISTRATION, Table 11 and During
Maintenance of Anesthesia).

Ultiva
has not been studied in pediatric patients for use as a postoperative analgesic
or as an analgesic component of monitored anesthesia care.

Geriatric Use

Of the total number of subjects in clinical studies
of Ultiva, 486 were 65 and over (age range 66 to 90 years). While the
effective biological half-life of remifentanil is unchanged, elderly patients
have been shown to be twice as sensitive as the younger population to the
pharmacodynamic effects of remifentanil. The recommended starting dose of
Ultiva should be decreased by 50% in patients over 65 years of age (see CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION).

Use in Morbidly Obese Patients

As for all potent opioids, caution is required with
use in morbidly obese patients because of alterations in cardiovascular and
respiratory physiology (see DOSAGE AND ADMINISTRATION).

Long-term Use in the ICU

No data are available on the long-term (longer than
16 hours) use of Ultiva as an analgesic in ICU patients.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal carcinogenicity studies have not been performed
with remifentanil.

Remifentanil did not induce
gene mutation in prokaryotic cells in vitro and
was not genotoxic in the in vivo rat
hepatocyte unscheduled DNA synthesis assay. No clastogenic effect was seen
in cultured Chinese hamster ovary cells or in the in
vivo mouse micronucleus test. In the in
vitro mouse lymphoma assay, mutagenicity was seen only with metabolic
activation.

Remifentanil has been shown to
reduce fertility in male rats when tested after 70+ days of daily IV administration
of 0.5 mg/kg, or approximately 40 times the maximum recommended human dose
(MRHD) in terms of mg/m2 of body surface area. The fertility of
female rats was not affected at IV doses as high as 1 mg/kg when administered
for at least 15 days before mating.

Pregnancy Category C

Teratogenic effects were not observed following
administration of remifentanil at doses up to 5 mg/kg in rats and 0.8 mg/kg
in rabbits. These doses are approximately 400 times and 125 times the MRHD,
respectively, in terms of mg/m2 of body surface area. Administration
of radiolabeled remifentanil to pregnant rabbits and rats demonstrated significant
placental transfer to fetal tissue. There are no adequate and well-controlled
studies in pregnant women. Ultiva should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.

Administration of remifentanil to rats throughout late gestation
and lactation at IV doses up to 5 mg/kg, or approximately 400 times the
MRHD in terms of mg/m2 of body surface area, had no significant
effect on the survival, development, or reproductive performance of the F1 generation.

Animal Toxicology

Intrathecal administration of the glycine formulation
without remifentanil to dogs caused agitation, pain, hind limb dysfunction,
and incoordination. These effects are believed to be caused by the glycine.
Glycine is a commonly used excipient in IV products and this finding has
no relevance for IV administration of Ultiva.

Labor and Delivery

Respiratory depression and other opioid effects
may occur in newborns whose mothers are given Ultiva shortly before delivery.
The safety of Ultiva during labor or delivery has not been demonstrated.
Placental transfer studies in rats and rabbits showed that pups are exposed
to remifentanil and its metabolites. In a human clinical trial, the average
maternal remifentanil concentrations were approximately twice those seen in
the fetus. In some cases, however, fetal concentrations were similar to those
in the mother. The umbilical arteriovenous ratio of remifentanil concentrations
was approximately 30% suggesting metabolism of remifentanil in the neonate.

Nursing Mothers

It is not known whether remifentanil is excreted
in human milk. After receiving radioactive-labeled remifentanil, the radioactivity
was present in the milk of lactating rats. Because fentanyl analogs are excreted
in human milk, caution should be exercised when Ultiva is administered to
a nursing woman.

ADVERSE EVENTS

Ultiva produces adverse events that are characteristic
of µ-opioids, such as respiratory depression, bradycardia, hypotension,
and skeletal muscle rigidity. These adverse events dissipate within minutes
of discontinuing or decreasing the infusion rate of Ultiva. See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS on the management of these events.

Adverse
event information is derived from controlled clinical trials that were conducted
in a variety of surgical procedures of varying duration, using a variety of
premedications and other anesthetics, and in patient populations with diverse
characteristics including underlying disease.

Adults

Approximately 2770 adult patients were exposed to
Ultiva in controlled clinical trials. The frequencies of adverse events during
general anesthesia with the recommended doses of Ultiva are given in Table
3. Each patient was counted once for each type of adverse event.

Table 3. Adverse Events
Reported in ≥ 1% of Adult Patients in General Anesthesia Studies* at
the Recommended Doses† of Ultiva

Induction/Maintenance

Postoperative
Analgesia

After
Discontinuation

* Does not include adverse
events from cardiac studies or the neonatal study. See Tables 6, 7, and 8
for cardiac information.

† See
Table 10 for recommended doses. Not all doses of
Ultiva were equipotent to the comparator opioid. Administration of Ultiva
in excess of the recommended dose (i.e., doses > 1 and up to 20 mcg/kg)
resulted in a higher incidence of some adverse events: muscle rigidity (37%),
bradycardia (12%), hypertension (4%), and tachycardia (4%).

‡ Included in the
muscle rigidity incidence is chest wall rigidity (5%). The overall muscle
rigidity incidence is < 1% when remifentanil is administered concurrently
or after a hypnotic induction agent.

Ultiva

Alfentanil/ Fentanyl

Ultiva

Morphine

Ultiva

Alfentanil /Fentanyl

Adverse Event

(n = 921)

(n = 466)

(n = 281)

(n = 98)

(n = 929)

(n = 466)

Nausea

8 (< 1%)

0

61 (22%)

15 (15%)

339 (36%)

202 (43%)

Hypotension

178 (19%)

30 (6%)

0

0

16 (2%)

9 (2%)

Vomiting

4 (< 1%)

1 (< 1%)

22 (8%)

5 (5%)

150 (16%)

91 (20%)

Muscle rigidity

98 (11%)‡

37 (8%)

7 (2%)

0

2 (< 1%)

1 (< 1%)

Bradycardia

62 (7%)

24 (5%)

3 (1%)

3 (3%)

11 (1%)

6 (1%)

Shivering

3 (< 1%)

0

15 (5%)

9 (9%)

49 (5%)

10 (2%)

Fever

1 (< 1%)

0

2 (< 1%)

0

44 (5%)

9 (2%)

Dizziness

0

0

1 (< 1%)

0

27 (3%)

9 (2%)

Visual disturbance

0

0

0

0

24 (3%)

14 (3%)

Headache

0

0

1 (< 1%)

1 (1%)

21 (2%)

8 (2%)

Respiratory depression

1 (< 1%)

0

19 (7%)

4 (4%)

17 (2%)

20 (4%)

Apnea

0

1 (< 1%)

9 (3%)

2 (2%)

2 (< 1%)

1 (< 1%)

Pruritus

2 (< 1%)

0

7 (2%)

1 (1%)

22 (2%)

7 (2%)

Tachycardia

6 (< 1%)

7 (2%)

0

0

10 (1%)

8 (2%)

Postoperative pain

0

0

7 (2%)

0

4 (< 1%)

5 (1%)

Hypertension

10 (1%)

7 (2%)

5 (2%)

3 (3%)

12 (1%)

8 (2%)

Agitation

2 (< 1%)

0

3 (1%)

1 (1%)

6 (< 1%)

1 (< 1%)

Hypoxia

0

0

1 (< 1%)

0

10 (1%)

7 (2%)

In the elderly population (> 65 years), the
incidence of hypotension is higher, whereas the incidence of nausea and vomiting
is lower.

Table 4.
Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia
Studies* at the Recommended Doses† of Ultiva

Induction/Maintenance

Postoperative
Analgesia

After
Discontinuation

* Does not include adverse
events from cardiac studies or the neonatal study.

† See Table 10 for recommended doses. Not
all doses of Ultiva were equipotent to the comparator opioid.